This invention relates to a method for the preparation of di, tri, and tetra fluorobenzenes as well as di, and trifluorochlorobenzenes by decarboxylation of the corresponding phthalic or benzoic acid. Such substituted benzenes have been prepared by several methods. For example, 1,2,3,4-tetrafluorobezene has been prepared by a number of methods. Banks, et. al. disclose a reaction in which 1,2,3,4,7,7-hexafluorobicyclo [2,2,1]hepta-2,5-diene rearranges to 1,2,3,4-tetrafluorobenzene upon being heated to 450.degree. C. (J. Fluor. Chem., 26 (1984) 169) the yield is reported to be 74%. Japanese Patent No. JP61047426 (1986) (as abstracted in Chem, Abs. 105:114709E) discloses a method for fluorination of 1,2,3,4-tetrachlorobenzene with a mixture of KF/CsF in benzonitrile at 350.degree. C. 1,2,3,4 tetrafluorobenzene is produced in 24.7% yield accompanied by partially fluorinated materials.
Finger et.al. report (J. Fluor. Chem. 2(1), 19 (1972) 1,2,4-trifluorobenzene may be prepared in 34% yield by the fluorination of 1,2,3,trichlorobenzene. Zweig, et. al. disclose (J. Org. Chem. 45, 3597 (1980) that 1-chloro-3,4-difluorobenzene may be prepared in 5.4% yield by treating 1,4-difluorobenzene with silver fluoride. The authors also obtained 1,2,4-trifluorobenzene in a 3% yield by an analogous reaction starting from 1,2-difluorobenzene. The polyfluorobenzenes and the fluoro-chlorobenzenes which are produced by the process of this invention have found uses as intermediates in a variety of pharmaceutical and agricultural applications. For example, 1,2,4 trifluorobenzene is a useful intermediate in the production of quinolone antibacterials. 1-chloro-3,4 difluorobenzene can be used to make quinolone antibacterials as well. In addition, the polyfluorobenzenes may be nitrated, and subsequently reduced to form fluorinated anilines which have found wide uses as pharmaceutical intermediates.
Many examples of decarboxylation reactions have been reported. Basic substances have been used to catalyze such reactions. For example, it is disclosed in D. S. Tarbell, et al Org. Syn., Coll. Vol. III (1955) 267, that 3,5-dichloro-4-hydroxybenzoic acid may be decarboxylated by vigorous heating in N,N-dimethylaniline. It is disclosed in A. Singer and S. M. McElvane, Org. Syn., Coll. Vol. II (1943) 214, that 3,5-dicarboxy-2,6-dimethylpyridine di-potassium salt may be completely decarboxylated by heating the salt in the presence of calcium hydroxide. Copper and copper salts have been used to catalyze decarboxylation reactions. For example, H. R. Snyder et al, Org. Syn., Coll. Vol. III (1955) 471 disclose the use of a copper oxide catalyst for the decarboxylation of imidazole 4,5-dicarboxylic acid.
Some compounds may be decarboxylated without catalysts. For example, C. Wang, Bul. Inst. Kim. Acad. Sinica, no. 2156 (1972), as abstracted in Chem. Abstracts (CA79 (15):91729), discloses that tetrachloro or tetrabromophthalic acids, or their anhydrides, may be decarboxylated to the corresponding benzoic acids when refluxed in dimethyl formamide. 3-Nitrophthalic acid underwent a similar reaction.
Decarboxylation is not always a predictable reaction. For example, A. S. Sultanov, J. Gen. Chem. (USSR) 16 1835 (1946) as abstracted in CA 41:6223(e) discloses that salicylic acid may be decarboxylated by autoclaving the acid in the presence of copper bronze and benzene at 170.degree. C. The acid alone decarboxylates at 205.degree. C., while in the presence of aniline decarboxylation begins at 170.degree. C. In the case of salicylic acid, aniline and copper bronze seem to be equal in catalytic ability. On the other hand, when phthalic acid is heated in aniline at 180.degree. C., decarboxylation does not occur and instead phthalic anhydride is produced. Heating phthalic anhydride with copper bronze in chloroform at 180.degree. C. gave a 22% yield of benzoic acid. Phthalic acid was found to decarboxylate to yield benzoic acid merely by heating in water at 235.degree. C.
Decarboxylations of certain fluorophthalic acids have been reported. 3,4,5,6-tetrafluorophthalic acid decarboxylates under certain conditions to yield 2,3,4,5-tetrafluorobenzoic acid. For example, Japanese Patent JP 61/85349 A2[86/85349]as abstracted in Chem. Abstracts (CA105:152719r), discloses that the reaction may be conducted in an aqueous medium at 150 to 230.degree. C. The reaction may be carried out at a lower temperature (100.degree. to 250.degree. C.) in the presence of copper, zinc, cadmium, iron, cobalt, nickel, other oxides, hydroxides and/or carbonates. Japanese Patent Application 86/103,317 as abstracted in Chem. Abstracts (CA105 (22):193368u), discloses that the above reaction may be conducted in an aqueous medium at a pH of 0.7-2.2 at a temperature of 100.degree.-200.degree. C. The pH of the medium is adjusted by acidifying with sulfuric acid and partial neutralization with calcium hydroxide. Japanese Patent 63/295529m A2[88/295529]as abstracted in Chem. Abstracts (CA 111 (3): 23221X), discloses that the reaction may be conducted at 130 in tri-butylamine.
Yacobsen, O. J. discloses in Zh. Obsch. Khim. 36 (1966) page 139 (as appearing in Journal of General Chemistry of the U.S.S.R. translated from Russian 36 (1966) page 144), that 2,3,4,5-tetrafluorophthalic acid may be decarboxylated to yield 2,3,4,5-tetrafluorobenzoic acid by heating for one hour at 145.degree. C. in dimethyl formamide solvent. See in addition United Kingdom Patent 2,122,190 (Inventors: David John Milner and Jerzy Czyzewski).
Japanese Patent JP 01/52737 as abstracted in Chem. Abstract (CA)111 (14):117305e discloses the preparation of 2,4,5-trifluorobenzoic acid by the decarboxylation of 3,4,6-trifluorophthalic acid in a liquid medium at a temperature of 80.degree.-250.degree. C.
Under slightly more vigorous conditions, Japanese Patent Application 61/43130 A2[86/43130]as abstracted in Chem. Abstracts (CA106 (1):46295), discloses that 3,4,5,6-tetrafluorophthalic acid may be completely decarboxylated to 1,2,3,4-tetrafluorobenzene. The conditions for complete decarboxylation are in an aqueous medium from 210.degree. to 300.degree. C., with no catalyst. In the presence of a catalyst, which may be metallic copper, zinc, cadmium, iron, cobalt or nickel, or the oxides, hydroxides or carbonates of those metals, the reaction may be run between 100.degree. and 270.degree. C. with the preferred range being 160.degree. to 200.degree. C. Impurities of trifluorophenol and 2,3,4,5-tetrafluorobenzoic acid were also produced.
Japanese Patent Application 86/290399 as abstracted in Chem. Abstracts (CA109 (19) 170038e), discloses that 3,5,6-trifluoro-4-hydroxyphthalic acid may be decarboxylated by heating the compound for three hours, in water, under nitrogen atmosphere, at 140.degree. C. (in a sealed tube) to yield 2,4,5-trifluoro-3-hydroxybenzoic acid.
Japanese Patent JP 1025737 as abstracted in Derwent (Acc. No. 89-073118/10), discloses that polyhalogenated phthalic acids may be decarboxylated to form polyhalogenated benzoic acids by heating the acid at a temperature of 100.degree.-200.degree. C., for 0.5 to 5 hrs., in the presence of a tertiary amine, and optionally in the presence of a nonpolar organic solvent. Further heating under the same conditions converts the polyhalobenzoic acid to a polyhalobenzene. Alternatively, the polyhalophthalic acids may be heated in the presence of the same reagents, at a temperature of 130.degree. to 270.degree. C. to yield polyhalobenzenes directly.
In our laboratories, attempts were made to prepare polyfluorobenzenes and fluorochlorobenzenes by decarboxylating the corresponding corresponding phthalic or benzoic acid. The decarboxylations proved to be difficult. The following table summarizes these experiments.
______________________________________ Decarboxylation of Various 4,5-Fluorophthalic and Fluorobenzoic Acids Compound Conditions Results ______________________________________ (1) 2,4,5 130.degree./80% H.sub.2 SO.sub.4 NR Trifluorobenzoic Acid (2) 2,3,4,5 200-210.degree. Diglyme/ NR Tetrafluorobenzoic Acid CuO Catalyst (3) 2,3,4,5 200-210.degree. Diglyme NR Tetrafluorobenzoic Acid Cu.sub.2 O Catalyst (4) 2,4,5 190.degree./DMSO NR Trifluorobenzoic Acid (5) 3,4,5,6 190.degree./DMSO Benzoic Acid Tetrafluorophthalic Acid formed (6) 3,4,5,6 150.degree. Tri-n- NR Tetrafluorophthalic Acid butylamine (7) 3,4,5,6 160.degree. Triethylamine/ NR Tetrafluorophthalic Acid Xylene (8) 3,4,5,6 160.degree. Tri-n- NR Tetrafluorophthalic Acid butylamine/Xylene ______________________________________ NOTE: NR means No Reaction Observed